This grant studies the molecular interaction between lung and adipose tissue mediated by the adipocyte-derived hormone adiponectin. Adiponectin has been shown to act in murine lung to tonically inhibit endothelial cell activation and to limit injury originating from endothelial cell damage (e.g. hyperoxia). This proposal will utilize a broad range of genetic tools (e.g. adiponectin and adiponectin receptor deficient mice) and reagents (e.g. recombinant adiponectin protein, adenoviral vectors) to perform the first comprehensive examination of adiponectin's role in lung vascular homeostasis. Studies in Aim 1 will identify the oligomeric fractions and key structural domains mediating adiponectin's effects on lung endothelium and will elucidate the down-stream signaling pathways of adiponectin on lung endothelium. Studies in Aim 2 are designed to test the hypothesis that adiponectin mitigates lung injury to hyperoxia by activating anti- inflammatory and cyto-protective processes on lung endothelium. Finally, studies in Aim 3 will utilize in vitro and in vivo tools to identify the important adiponectin receptor mediating adiponectin's effects in lung. Taken together, studies in this grant will identify the molecular mechanisms by which APN regulates lung vascular processes in the hope of identifying new avenues of research in lung vascular biology and laying the foundation for the rational design of future clinical investigations examining APN in human lung disease. PUBLIC HEALTH RELEVANCE: This grant introduces the novel concept that an adipocyte-derived hormone called adiponectin regulates homeostatic suppression of lung endothelium and mitigates lung injury originating from endothelial cell damage. Studies in this proposal aim to elucidate the molecular mechanisms mediating adiponectin's effects on murine lung endothelium in order to identify new strategies for developing novel therapies for prevention and treatment of human lung vascular disease.